Journal Article

Seven mutations in the human insulin gene linked to permanent neonatal/infancy-onset diabetes mellitus

Porzio, Ottavia, Federici, Luca, Liu, Ming, Colombo, Carlo, Vasta, Mario, Arvan, Peter, Federici, Giorgio, Cadario, Francesco, Iafusco, Dario, Barbetti, Fabrizio, Pedersen, Oluf, Pesavento, Roberta, Hansen, Torben, Massa, Ornella, Salardi, Silvana, Beccaria, Luciano, Ghirri, Paolo, Monciotti, Carla, Toni, Sonia

2008

Overview

Permanent neonatal diabetes mellitus (PNDM) is a rare disorder usually presenting within 6 months of birth. Although several genes have been linked to this disorder, in almost half the cases documented in Italy, the genetic cause remains unknown. Because the Akita mouse bearing a mutation in the Ins2 gene exhibits PNDM associated with pancreatic beta cell apoptosis, we sequenced the human insulin gene in PNDM subjects with unidentified mutations. We discovered 7 heterozygous mutations in 10 unrelated probands. In 8 of these patients, insulin secretion was detectable at diabetes onset, but rapidly declined over time. When these mutant proinsulins were expressed in HEK293 cells, we observed defects in insulin protein folding and secretion. In these experiments, expression of the mutant proinsulins was also associated with increased Grp78 protein expression and XBP1 mRNA splicing, 2 markers of endoplasmic reticulum stress, and with increased apoptosis. Similarly transfected INS-1E insulinoma cells had diminished viability compared with those expressing WT proinsulin. In conclusion, we find that mutations in the insulin gene that promote proinsulin misfolding may cause PNDM.

• Publisher: American Society for Clinical Investigation
• Subject: Amino Acid Sequence / Apoptosis / Biomedical research / Complications and side effects / Diabetes / Diabetes Mellitus - genetics / Diseases / DNA Mutational Analysis / DNA-Binding Proteins - biosynthesis / Endoplasmic Reticulum Chaperone BiP / Female / Gene mutations / Genes / Genetic aspects / Health aspects / Heat-Shock Proteins - biosynthesis / Heterozygote / Humans / Infant / Infants (Newborn) / Insulin - genetics / Insulin - physiology / Insulin resistance / Male / Molecular Chaperones - biosynthesis / Molecular Sequence Data / Mutation / Nuclear Proteins - biosynthesis / Pancreatic beta cells / Pedigree / Peptides / Proinsulin - biosynthesis / Regulatory Factor X Transcription Factors / Risk factors / Transcription Factors / X-Box Binding Protein 1